Regulatory T cells (Tregs) play a crucial role in preventing autoimmunity, limiting immunopathology and maintaining immune homeostasis1. However, they also represent a major barrier to effective anti-tumor immunity and sterilizing immunity to chronic viral infections. This highlights the capacity of Tregs to shape and control a wide range of immune responses. Foxp3 is a master transcriptional regulator required for the development, maintenance and stability of Tregs2,3. Mice and humans with non-functional Foxp3 lack Tregs and develop a lethal systemic autoimmune condition, referred to as Scurfy in mice and IPEX in humans, highlighting the importance of Tregs in the maintenance of immune homeostasis2,3. Furthermore, a transcription factor quintet forms a redundant genetic switch to ‘lock-in’ the Treg transcriptional signature and enhance their stability4. Although some external factors, such as transforming growth factor-β (TGFβ), have been shown to maintain and/or enhance Foxp3 stability and function5, it is unknown if additional cell-extrinsic pathways or factors exist.
Tissue-resident Tregs are some of the first lymphoid cells to respond to an infection or inflammatory response, thereby limiting immune pathology6,7. Some environments, such as tumors and chronic infections, can be highly inflammatory and thus may require additional mechanisms or genetic programs to enhance the stability and function of Tregs in order to limit unintended inflammatory or autoimmune disease. Consequently there is considerable interest in identifying molecular pathways that control Treg stability and function as many immune-mediated diseases are characterized by either exacerbated or limited Treg function, and the adoptive transfer of Tregs for the treatment of a variety of diseases is being actively pursued in the clinic.
Treg stability versus plasticity has been a topic of considerable recent debate. Some studies have defined critical roles for lineage-specific transcription factors, such as T-bet, IRF4 and STAT3, in regulating specific types of T cell responses driven by the same transcription factors8-10. In contrast, others have suggested that a demonstrable proportion of Tregs differentiate in inflammatory sites into ‘ex-Tregs’ and gain effector function11. The cell-extrinsic factors and molecular mechanisms by which Tregs alter their transcriptional profile to maintain their stability, regulate immunity in inflammatory sites and control these alternate cell fates remain obscure.
Neuropilin-1 (Nrp1; see, e.g., GenBank Accession Nos. NM_008737 (mouse) and NG_030328 (human) as well as various isoforms) is a membrane-bound coreceptor to a tyrosine kinase receptor for both vascular endothelial growth factor (VEGF) and class III semaphorin Sema3a. Nrp1 plays versatile roles in axon guidance, angiogenesis, cell survival, migration, and invasion15. Nrp1 induces axon growth cone collapse, preventing infiltration into privileged tissues and its genetic deletion in mice results in embryonic lethality16. Nrp1 has been also shown to interact platelet derived growth factor beta (PDGFβ) and transforming growth factor beta (TGFβ)17,18. Nrp1 has been shown to be highly expressed in Tregs19-21. Although a role for Nrp1 in T cells has been implicated22, no role for Nrp1 in Tregs has been identified and it has been suggested that Nrp1 is not expressed on human Tregs25.